Substituted indenyl acetic acids in the treatment of pain, fever or inflammation

ABSTRACT

New substituted indenyl acetic acids and nontoxic pharmaceutically acceptable amides, esters and salts derived therefrom. The substituted indenyl acetic acids disclosed herein have anti-inflammatory, anti-pyretic and analgesic activity. Also included herein are methods of preparing said indenyl acetic acid compounds, pharmaceutical compositions having said indenyl acetic acid compounds as an active ingredient and methods of treating inflammation by administering these particular compositions to patients.

United States Patent 1 1111 3,725,548

Shen et a1. Apr. 3, 1973 [54] SUBSTITUTED INDENYL ACETIC ACIDS IN THETREATMENT OF PAIN, [56] References Cited R INFLAMMATI N FEVER 0 0 UNITEDSTATES PATENTS [75] Inventors: Tsung-Ying Shen, Westfield, N.J.;

Richard Greenwald, 3,312,730 4/1967 Winters et a1. ..260/470 XFramingham, Mass; Howard Jones, Holmdel NJ; Bruce 0. Linn, FOREIGNPATENTS OR APPLICATIONS Somerville, N.J.; Bruce E. Witzell, 1,178,6581/1970 Great Britain Westtield, NJ. 1,815,451 7/1969 Germany [73]Assignee: Merck & Co., Inc., Rahway, NJ. Primary Examiner stanley LFriedman [22] Filed: Oct. 6, 1971 Att0meyMartin L. Katz et al.

[21] Appl. No.: 187,197 ABSTRACT Related Application Data Newsubstituted indenyl acetic acids and nontoxic [60] ivision fSe No,33,391, May 1 970, p Nu pharmaceutically acceptable amides, esters andsalts 3,654,349, which is a cOntinuatiQmin-part of Ser. No. derivedtherefrom. The substituted indenyl acetic 8- 3, 1969,3band0fledacidsdisclosed herein have anti-inflammatory, antipyretic and analgesicactivity. Also included herein US. Cl. are methods of preparing saidindenyl acetic acid 424/263, 424/270, 424/275, 424/235, compounds,pharmaceutical compositions having said 424/304 424/308 424/309, 424/317indenyl acetic acid compounds as an active ingredient 424/324 andmethods of treating inflammation by administer- [51] Int. Cl. theseparticular compositions to patients. [58] Field of Search ..424/304,308, 309, 311, 316,

20 Claims, N0 Drawings CROSS REFERENCES TO RELATED APPLICATIONS Thisapplication is a division of copending U.S. application Ser. No. 33,891filed May 1, 1970 now U.S. Pat.

No. 3,654,349 which, in turn, is a continuation-in-part of U.S. Ser. No.848,736, filed Aug. 8, 1969 now abandoned.

BACKGROUND OF THE INVENTION The development of anti-inflammatorycompounds in the past two decades has seen the growth of a great manynew drugs. Most of these have been steroids of the l l-oxygenatedpregnane series. These, while highly effective as anti-inflammatoryagents, have many side effects. More recently, nonsteroidalanti-inflammatory compounds, such as the idenyl, indolyl and salicylicacids, of much simpler structure than the steroidal antiinflammatorycompounds have been developed.

An object of this invention is the development of new potentanti-inflammatory compounds. A further object of this invention is thedevelopment of anti-inflammatory compounds having an increasedtherapeutic index. A still further object of this invention is thedevelopment of anti-inflammatory compounds which are highly desirabletherapeutic agents in that metabolism of the drug in the body will notresult in the formation of undesirable insoluble products which mayimpair the functioning of the renal system. Another object of thisinvention is the development of potent analgesic compounds.

SUMMARY OF THE INVENTION Generally, this invention relates to newsubstituted indenyl acetic acid compounds and processes for producingthe same. This invention also relates to pharmaceutical compositionscontaining said indenyl acetic acid compounds as an active ingredientand to methods of treating pain, fever or inflammation by administeringthese particular compositions to patients.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention relates to newsubstituted indenyl acetic acids and processes for producing the same.More specifically, this invention relates to substituted indenyl aceticacids, amides, esters and non-toxic pharmaceutically acceptable saltsthereof. Still more specifically, this invention relates to compoundshaving the following general formula:

wherein:

may be aryl or heteroaryl; 1 may be hydrogen, loweralkyl or halogenatedloweralkyl;

R may be hydrogen or alkyl;

R R R and R each may be hydrogen, alkyl,

acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino,dialkylaminoalkyl, sulfamyl, alkylthio, mercapto, hydroxy, hydroxyalkyl,alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido,halogenoalkyl, cycloalkyl or cycloalkoxy;

R may be alkylsulfinyl or alkylsulfonyl;

R may be hydrogen, halogen, hydroxy, alkoxy, or

halo-alkyl; and

M may be hydroxy, loweralkoxy, substituted loweralkoxy, amino,alkylamino, dialkylamino, N-

morpholino, hydroxyalkylamino, polyhydroxyal kylamino,dialkylaminoalkylamino, aminoalkylamino, and the group oMe, in which Meis a cation.

The indene nucleus may be substituted in the l-position by an aryl ringsystem such as benzene, napthalene or biphenyl or a heteroaryl ringsystem such as a pyrrole, furan, thiophene, pyridine, imidazole,pyrazine, thiazole, etc. which contains an alkylsulfinyl oralkylsulfonyl substituent and may be further substituted with a halogen(chloro, fluoro or bromo), hydroxy, alkoxy (methoxy, ethoxy, propoxy,etc.) or haloalkyl (fluoromethyl, chloromethyl, trifluoromethyl, etc.)group.

In the most preferred compounds of this invention R R R and R each maybe halogen (fluoro, chloro or bromo), loweralkoxy (methoxy, ethoxy,i-propoxy, etc.) loweralkyl (methyl, ethyl, propyl, isopropyl, etc.),nitro, amino or substituted amino such as dialkylamino, acylamino,alkylamino, etc. R R R and R are not however limited to this class andmay, if desired, represent substitutents such as hydrogen, aryl,aryloxy, hydroxy, mercapto, haloalkyl, sulfamyl, carboxy, carboalkoxy,carbamido and many other groups.

Representative compounds of this invention are as follows:

5 -I-I ydroxy-2-methyll -p-methylsulfinylbenzylidene- 3-indene aceticacid;

S-Methoxy-Z-methyl-l-p-methylsulfinylbenzylidene- 3-indene acetic acid;

5 -Fluoro-2-methyll -p-methylsulfinylbenzylidene-3- indene acetic acid;

a-( S-Fluoro-2-methyl- 1 -p-methylsulfinylbenzylidene-S-indene)propionicacid;

5 ,6-Difluoro-2-methyll -p-methylsulfinylbenzylidene-3-indene aceticacid;

S-ChIoro-Z-methyl-1-p-methylsulfinylbenzylidene-3- indene acetic acid;

5 -Trifluoromethyl-2-methyll -p-methylsulfinylbenzylidene-3-indeneacetic acid;

S-Methyl-Z-methyl-l-p-methylsulfinylbenzyIidene-3- indene acetic acid;

5 ,7-Difluoro-2-methyll -p-methylsulfinylbenzylidene-3-indene aceticacid;

a-( 5 ,7-Difluoro-2-methyll-p-methylsulfinylbenzylidene-3-indene)propionic acid;

5-Dimethylamino-6-fluoro-2-methyl-I-p-methylsulfinylbenzylidene-3-indene acetic acid;

5-Methoxy-6-fluoro-2-methyl-l-p-methylsulfinylbenzylidene-3-indeneacetic acid;

a-( S-Methoxy-6-fluoro-2-methyl- 1 -p-methylsulfinylbenzylidene-3-indene)propionic acid;

a-( 5,6-Difluoro-2-methyl-1-p-methylsulfinylbenzylidene-3-indene)propionicacid;

-Methoxy-2-methyll -p-methylsulfonylbenzylidene-3-indene acetic acid;

5-Fluoro-2-methyl-l -p-methylsulfonylbenzylidene- 3-indene acetic acid;

5,6-Difluoro-2-methyl-l-p-methylsulfonylbenzylidene-3-indene aceticacid;

5,7-Difluoro-2-methyl-l-p-methylsulfonylbenzylidene-3-indene aceticacid;

5-Dimethylamino-6-fluoro-2-methyll -p-methylsulfonylbenzylidene-3-indeneacetic acid;

5 -Methoxy-6-fluoro-2-methyll -p-methylsulfonylbenzylidene-3-indeneacetic acid;

a-(2-Methyl-5,6-difluoro-l-p-methylsulfonylbenzylidene-3-indene)propionicacid; and the corresponding amides, esters and salts.

It should be noted that the compounds of this invention may beisomerized into their cis and trans isomers by procedures well known inthe art. It should be further noted that the cis isomer of the compoundsof this invention is substantially more active than the trans isomer.Accordingly, it is to be understood that reference throughout thespecification and appended claims to the compounds of this invention isintended to encompass not merely the compounds per se but includes theirgeometric isomers (cis, trans).

It should be further noted by one skilled in the art that thealkylsulfinyl derivatives of this invention are racemic mixtures ofoptically active enantiomorphs which may be resolved into their andforms by techniques well known in the art. Furthermore, when R isloweralkyl an additional asymmetric atom results which gives rise to twoadditional enantiomorphs, which are also considered to be within thescope of the invention.

One skilled in the art should further note that some of the compounds ofthis invention are polymorphic and have different crystallinestructures, melting points and solubility characteristics.

This invention also relates to a method of treating pain, fever orinflammation in patients using a compound of Formula I, particularly anespecially preferred compound as the active constituent.

The compounds of the instant invention can be used to treat inflammationby reducing inflammation and relieving pain in such diseases asrheumatoid arthritis, osteoarthritis, gout, infectious arthritis andrheumatic fever. The compounds of the instant invention have betterpotency at the same dosage levels than similar type compounds known inthe prior art and exhibit a lower incidence of ulcerogenic side effects.Furthermore, the compounds of the instant invention are substantiallymore water-soluble than similar prior art compounds.

The compounds of Formula I also have anti-pyretic and analgesic activityand would be administered and used in the same manner and in the samedosage ranges as if they were being used to treat inflammation asdiscussed further on.

The treatment of inflammation in accordance with the method of thepresent invention is accomplished by topically, orally, rectally orparenterally administering to patients a composition of a compound ofFormula I, particularly the especially preferred compounds in anon-toxic pharmaceutically acceptable carrier.

The non-toxic pharmaceutical carrier may be, for example, either a solidor a liquid. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, cab-o-sil, and acacia. Exemplary of liquidcarriers are peanut oil, olive oil, sesame oil and water. Similarly, thecarrier or diluent may include a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, ifa solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup, an aqueous solution or a liquid suspension. Suppositories may beprepared in a conventional manner by mixing the compounds of thisinvention with a suitable non-irritating excipient which is solid atroom temperature, but liquid at the rectal temperature. Such materialsare cocoa butter and polyethylene glycol. Gels and lotions for topicalapplication may be prepared in conventional manners.

The active compounds of Formula I and of the compositions of thisinvention are administered in an amount sufficient to treatinflammation, that is to reduce inflammation. Advantageously, thecompositions will contain the active ingredient, namely, the compoundsof Formula I in an amount of from about 0.1 mg. to 50 mg. per kg. bodyweight per day (5 mg. to 3.5 g. per patient per day), preferably fromabout 1 mg. to 15 mg./kg. body weight per day (50 mg. to l g. perpatient per day).

The method of treatment of this invention comprises administering to apatient (animal or human), a compound of Formula I, particularly anespecially preferred compound admixed with a non-toxic pharmaceuticalcarrier such as exemplified above. The compounds of Formula I andparticularly the especially preferred compounds will be administered inan amount of from 0.1 mg. to 50 mg./kg. body weight per day, preferablyfrom about 1 mg. to about 15 mg. per kilogram body weight per day. Themost rapid and effective anti-inflammatory effect is obtained from oraladministration of a daily dosage of from about I to 15 mg./kg./day. Itshould be understood, however, that although preferred dosage ranges aregiven, the dose level for any particular patient depends upon theactivity of the specific compound employed. Also many other factors thatmodify the actions of drugs will be taken into account by those skilledin the art in the therapeutic use of medicinal agents, particularlythose of Formula I, for example, age, body weight, sex, diet, time ofadministration, route of administration, rate of excretion, drugcombination, reaction sensitivities and severity of the particulardisease.

In the preparation of the compounds of this invention, the startingmaterial is a B-aryl propionic acid. This compound is prepared accordingto the procedure shown in Flow Sheet I which illustrates severalalternative routes. Thus, a substituted benzaldehyde may be condensedwith a substituted acetic ester in a Claisen Reaction or with ana-halogenated propionic ester in a Reformatsky Reaction. The resultingunsaturated ester is reduced and hydrolyzed to give the benzyl propionicacid starting material. Alternatively, a substituted malonic ester in atypical malonic ester synthesis and acid hydrolysis of the resultingsubstituted ester yields and benzyl propionic acid directly or thebenzaldehyde may be reacted with propionic anhydride in a reducingmedium to form the benzyl propionic acid. Equivalents:

X is halogen, usually C1 or Br;

E is esterifying group, usually methyl, ethyl or benzyl;

R is hydrogen or alkyl;

R R R and R each may be hydrogen, alkyl,

acyloxy, alkoxy, nitro, amino, acylamino, alkylarnino, dialkylamino,dialkylaminoalkyl, sulfamyl, halogen, alkylthio, mercapto, hydroxy,hydroxyalkyl, alkylsulfonyl, cyano, carboxyl, carbalkoxy, carbamido,halogenoalkyl, cycloalkyl, or cycloalkoxy.

Reagentsz 1. Zn dust in anhydrous inert solvent such as benzene andether.

2. KHSO or p-toluene sulfonic acid.

3. NaOCJ-l is anhydrous ethanol at room temperature.

4. H palladium on charcoal, 40 p.s.i., room temperature.

5. NaOH in aqueous alcohol at -l00.

6. NaOC H or any other strong base such as NaOH or K-t-butoxide.

7. Acid.

1. Preparation of fl-arylpropioni'c acid starting material.

In the preparation of the compounds of the instant invention, again anumber of routes are possible, as

5 acid. The indanone may be condensed with an a-halo ester in theReformatsky Reactionto introduce the aliphatic acid side chain byreplacing the carbonyl group. Alternatively, this introduction can becarried out by the use of a Wittig Reaction in which the reagent is ana-triphenylphosphinyl ester, a reagent which replaces the carbonyl witha double bond to a carbon. This is immediately rearranged into theindene. If the Reformatsky Reaction route is used, the intermediate3-hydroxy-3-aliphatic acid derivative must dehydrated to the indene. Theintroduction of the 1- substituent is carried out in one of two ways.The first is the direct reaction of the indene with the aldehyde of thestructural characteristics defined, using a strong base as a catalystand warming, if necessary, to form the carbanion. The reaction can becarried out in a number of solvents such as polar solvents likedimethoxyethane, aqueous methanol, pyridine, liquid ammonia,dimethylformamide and the like or even in non-polar solvents such asbenzene, etc. Alternatively, an indanone can be brominated and thendehydrogenbrominated to an indenone and the indenone carbonyl replacedby the substituent using the a-triphenyl-phosphinyl compounds of thedesired structure. Note that E in the third stage and in the fifth stageis a loweralkoxy group and thus forms a loweralkyl ester of the desiredcompound. This ester can then be hydrolyzed to give the free acids andoxidized to give the sulfoxides and sulfones from which the salts, otheresters and the amides may be formed. Step 6 can also be carried out whenE is hydrogen. Equivalents:

X, E, R R R and R are the same as in Flow Sheet R is hydrogen,loweralkyl or halogenated loweral- 20-l20bL in ether, benzene, toluene,xylene, etc. Reaction with aldehyde or ketone, using strong base ascatalyst (K-t-butoxide or any alkoxide, NaOH, KOH, NaNH etc.), warmingif necessary to form the carbanion in solvents such as liquid ammonia,dimethylformamide, 1,2-dimethoxyethane, pyridine, aqueous alcohol, etc.

ll. Preparation of a-(l-substituted-methylenyl-3-indenyl)aliphaticacids.

(1n, (III 00}! Although the synthesis described produce esters of theacids of this invention, some desired esters are more easily obtained byforming a simple ester of the final acid, hydrolyzing to the free acidand re-esterifying. The simple loweralkyl or benzyl esters are usuallythe ones used in the synthesis of the compounds. Other esters are moredesirable from the standpoint of therapeutic utility of the compounds,such as the methoxymethyl, diethylaminoethyl, dimethylaminoethyl,dimethylaminopropyl, diethylaminopropyl, N-pyrollidinylethyl, N-piperidinylethyl, N-morpholinylethyl, N-ethyl-2- piperidinylethyl,N-pyrrolidinylmethyl, N-methyl-2- pyrollidinylmethyl, 4-methyll-piperazinylethyl, methoxyethyl, ethoxyethyl, and the like. These aremostly prepared from the corresponding alcohol and the indenyl acid.

The amines, both the simple amide and the substituted amides, aresimilarly prepared from the indenyl acids and the corresponding amines.Especially useful therapeutically are the morpholide, thebis(hydroxyethyl)amide and the like.

Similarly, salts are obtained by neutralizing the indenyl acids withbases or by methathesis of other salts. Especially useful are themetallic salts such as the alkali metal or alkaline earth salts and theamine and quaternary ammonium salts, which are water soluble, but theheavy metal salts such as iron, alumminum, etc. are also useful for somepurposes.

The following examples are presented to further illustrate theinvention:

EXAMPLE 1 a-Methyl-fi-(p-methylthiophenyl)propionic acid To a solutionof 2.3 g. (0.1 mole) of sodium in ml. of absolute alcohol is added 17.4g. (0.1 mole) of diethyl methylmalonate and 17.3 g. (0.1 mole) ofpmethylthiobenzylchloride. The mixture is heated under a reflux in awater bath for 3 hours. The reaction mixture is poured into water andthe aqueous solution is extracted six times with ether and dried. It isthen evaporated to yield diethyl methyl-p-methylthiobenzyl malonate. Thecrude product is then saponified by heating with excess 4 percent sodiumhydroxide in aqueous ethanolic solution. The solution thus formed is:

H. 6-Methoxy-2-methylindanone a-Methyl-B-(p-methoxyphenyl)propionic acid(15 g.) is added to 170 g. of polyphosphoric acid at 50 and the mixtureis heated at 8390 for 2 hours. The syrup is poured into iced water,stirred for one-half hour and then extracted with ether three times. Theether solution is washed with water twice and 5% NaHCO five times untilall the acidic material has been removed. The remaining neutral solutionis washed with water and dried over sodium sulfate. Evaporation of thesolution gives the indanone as a pale yellow oil.

In a similar manner, other a-aryl propionic acid compounds are convertedto the corresponding indanone by the procedure of this example.

C. Methyl-5-methoxy-2-methyl-3-indenylacetate A solution of 13.4 g. of6-methoxy-2-methylindanone and 19.3 g. of methyl bromoacetate in 45 ml.benzene is added over a period of 5 minutes to 21 g. of zinc amalgam(prepared according to Org. Syn. ColL, vol. 3) in ml. benzene and 40 ml.dry ether. A few crystals of iodine are added to start the reaction, andthe reaction mixture is maintained at reflux temperature (ca. 65) withexternal heating. At 3 hour intervals two batches of 10 g. zinc amalgamand 10 g. bromoester are added and the mixture is then refluxed for 8hours. After addition of 30 ml. of ethanol and ml. of acetic acid, themixture is poured into 700 ml. of 1:1 aqueous acetic acid. The organiclayer is separated, and the aqueous layer is extracted twice with ether.The combined organic layers are washed thoroughly with water, ammoniumhydroxide and water. Drying over sodium sulfate, evaporation of solventin vacuo followed by pumping at 80 (bath temp.) (1-2 mm.) gives crudemethyl (1-hydroxy-2-methyl-6-methoxy-indenyl)acetate.

A mixture of the above crude hydroxyester, 20 g. of p-toluenesulfonicacid monohydrate and 20 g. of anhydrous calcium chloride in 250 m1.toluene is refluxed overnight. The solution is filtered and the solidresidue is washed with benzene. The combined benzene solution is washedwith water, sodium bicarbonate, water and then dried over sodiumsulfate. After evaporation the crude methyl -methoxy-2-methyl-3-indenylacetate is chromatographed on acid-washed alumina, and the productis eluted with petroleum etherether (v./v. 50-l00%). Methyl2,5-dimethyl-3-indenylacetate The above reactions of Example 1C arerepeated except that the starting materials are 2,5-dimethy1indanone andmethylbromoacetate. Using the same reaction conditions and techniquesthere is obtained methyl 2,6-dimethyl-3indenylacetate.

The above reactions of Example 1C are repeated except that the startingmaterials are 6-methylthioindanone and methylbromoacetate. Using thesame reaction conditions and techniques, there is obtained methyl5-methylthio-2-methyl-3-indenylacetate.

When any of the other indanones described in the other examples of thespecification are used in the above procedure in place of6-methoxy-2-methylindanone the corresponding methyl ester is obtained.

D. 5-Methoxy-2-methyl-l (p-methylthiobenzylidene)- 3-indenyl aceticacid.

To a solution of methyl 5-methoxy-2-methyl-3-indenylacetate 8.7 g.(0.037 mole) and pmethylthiobenzaldehyde, 6.3 g. (1.1 equivalent) isadded l6 ml. (2.0 equivalents) of 25 percent methanolic sodiummethoxide. The mixture is stirred at reflux under nitrogen for 2 hours.An equal volume of water is added dropwise and refluxing continues for30 min. The solution is cooled, diluted with water and extracted withether (3X). Residual ether is blown off with nitrogen and then theaqueous solution is acidified with 50 percent glacial acetic acid. Theprecipitated product is collected and washed thoroughly with water. Thecrude product is crystallized from methanol to give pureS-methoxy-Z-methyll -(p-methylthiobenzylidene)-3-indenylacetic acid(m.p. l95196). 5-Methoxy-2-methyl-l-(p-ethylthiobenzylidene)-3-indenylacetic acid r The above reaction of Example 1D is repeated usingp-ethylthiobenzaldehyde instead of pmethylthiobenzaldehyde. Using thesame reaction conditions and techniques, there is obtained 5-rnethoxy-2-methyl- 1 p-ethylthiobenzylidene )-3-indenyl acetic acid.5-Hydroxy-2-methyl-l-(p-methylthiobenzy1idene)-3- indenyl acetic acidThe reaction of Example 1D is repeated except that the startingmaterials are methyl 5-hydroxy-2-methyl-3 -indenylacetate andp-methylthiobenzaldehyde. Using the same reaction conditions andtechniques, there is obtained5-hydroxy-2-methyl-1-p-methylthiobenzylidene)-3-indenyl acetic acid.

The other methyl esters of Example lCare reacted withp-methylthiobenzaldehyde according to the above procedure to produce thecorresponding indenyl acetic acid.

E. S-MethoXy-Z-methyI-l-(pmethylsulfinylbenzylidene )-3-indenylaceticacid A solution of sodium periodate (0.214 g.) (0.001 mole) in 3 ml. ofwater is added dropwise to S-methoxy-2-methyl-l-(p-methylthiobenzylidene)-3-indenylacetic acid (0.352 g.)(0.001 mole) in 25 ml. methanol and enough acetone to cause solution.This solution is stirred overnight at room temperature and filtered. Thefiltrate is evaporated at 30 to a small volume which causes the productto precipitate. The suspension is diluted with several volumes of water,cooled and collected. The product is dried in vacuo over potassiumhydroxide pellets and then in a vacuum oven at to give5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid(m.p. 200.5-203.5).

5-Methoxy-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acidis prepared by the addition of 1.0 mole of m-chloroperbenzoic acid permole of 5- methoxy-Z-methyll -(p-methylsulfinylbenzylidene )-3indenylacetic acid in an acetone solution.

EXAMPLE 2 A. 6-Methoxy-2-methylindanone in a 500 ml. three-necked flaskis placed 36.2 g. (0.55 mole) of zinc dust and in a 250 ml. additionfunnel is charged a solution of ml. anhydrous benzene, 20 ml. ofanhydrous ether, 80 g. (0.58 mole) of panisaldehyde and 98 g. (0.55mole) of ethyl-2- bromopropionate. About 10 ml. of the solution is addedto the zinc dust with vigorous stirring and the mixture is warmed gentlyuntil an exothermic reaction commences. The remaining reactants areadded dropwise at such a rate that the reaction mixture is refluxingsmoothly on its own accord (ca. 30-35 min.). After addition is completedthe mixture is placed in a water bath and refluxed for 30 minutes. Aftercooling to 0, 250 ml. of 10 percent sulfuric acid is added with vigorousstirring. The benzene layer is extracted twice with 50 ml. portions of 5percent sulfuric acid and washed twice with 50 ml. portions of water.The aqueous acidic layers are combined and extracted with 2 X 50 ml.ether. The combined ethereal and benzene extracts are dried over sodiumsulfate. Evaporation of solvent and fractionation of the residue througha 6 inch Vigreux column affords the product, ethyl 2-hydroxy-(p-rnethoxyphenyl)- 1 -methylpropionate, b.p. -16 0 1.5 min.). I

By the method described in Vander Zanden, Rec. trav. chim., 6 8, 413(1949), the above compound is converted to 6-methoxy-2-methylindanone.5-Ethyl-2-methylindanone The above reactions of Example 2A are repeatedexcept that the starting materials are o-ethylbenzaldehyde andethyl-2-bromopropionate. Using the same reaction conditions andtechniques there is obtained 5- ethyl-2-methylindanone.

When the following benzaldehydes are utilized in the procedure ofExample 2A, the corresponding indanone is obtained:

p-, o-, or m-hyd'roxybenzaldehyde I p-, o-, or m-nitrobenindanone2methyl-(4,5 or 6)-nitroaldehyde p-, o-, or m-chlorobenzaldehyde p-, o-,or m-cyanobenzaldehyde Vanillin p-, o-, or m-sulfamylbenzaldehyde3-chloro-4-methylbenzaldehyde 4-carbamido-5-methylbenzaldehyde3,4-difluorobenzaldehyde indanone (4,5 or 6)-chloro-2- methylindanonc(4,5 or 6)-cyano-2- methylindanone 6-hydroxy-5-methoxy-2- methylindanone2-methyl-(4,5 or 6)-sulfamylindanone ch1oro-2,6-dimethylindanone6'carbamido-2,S-dimethylindanone 5 ,6-difluoro-2-methylinda B. 5-Methoxy-Z-methyl- 1 -(pmethylsulfinylbenzylidene)-3-indenylacetic acidThe reactions of Example 1C, 1D and 1E are repeated and5-methoxy-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetic acidis obtained.

EXAMPLE 3 A. Methyl a-(5-methoxy-2-methyl-3- indenyl)propionate samemanner.

B. a-[1-(p-Methylthiobenzylidene)-2-methyl-5-methoxy-3-indenyl]propionic acid To a solution of 0.5 g. (0.00192 mole)of methyl a- (5-methoxy-2-methyl-3-indenyl)propionate and 0.595 g.(0.0039 mole) of p-methylthiobenzaldehyde in 3 ml. of anhydrous pyridineis added 1.63 g. of a 40 percent solution of benzyltriniethylammoniumhydroxide (Triton-B) in methanol. The resulting red-purple solution isallowed to stir at room temperature overnight.

The reaction mixture is poured into a mixture of ice and water,acidified with 2.5 N HCl and extracted with ether. The ethersolution isthen washed with 2.5 N HCl until the washing acidifies (once), then withwater until neutral. The ether layer is then extracted with 5 percent NaCO solution. The Na CO solution is washed with ether, acidified andextracted with ether. The ether solution is washed with water, driedover Na SO and concentrated in vacuo to a yellow oil which foams up to aclear yellow solid on pumping at O.5-1 mm. Thin layer chromatography ofthe product shows only one spot when eluted with a (v./v. 413:5) ofisopropanol: NH OH: ethyl acetate mixture:

U.V. absorption: Amax. 3525, 2910, 2540, 2450. 13% 399, 260, 510 and498.

C. a-[1-(p-Methylsulfinylbenzylidene)-2-methyl-5-methoxy-3-indenyl]-propionic acid The procedure of Example IE isfollowed using a-[ 1-(p-methylthiobenzylidene)-2-methyl-5-methoxy-3-indenyl]-propionic acidin place of 5-methoxy-2-methyl-1-(p-methylthiobenzylidene)-3-indenylacetic acid thereby producinga-[1-(p-methylsulfinylbenzylidene)-2-methyl-5-methoxy-3-indenyll-propionic acid (m.p. l l5-l20).

a-[ l-(p-Methylsulfonylbenzylidene)-2-methyl-5-methoxy-3-indenyl]-propionic acid is produced by the addition of 1.0mole of m-chloroperbenzoic acid per mole ofa-[1-(p-methylsulfinylbenzylidene)-2-methy1-5-methoxy-3-indenyl]-propionic acid as described in Example 1E.

EXAMPLE 4 A. Methyl 3-hydroxy-2-methyl-5-nitro-3- indenylacetate Theprocedure of Example 1C is followed using 2- methy1-6-nitro indanone inequivalent quantities in place of 6-methoxy-2-methyl indanone usedtherein. After the mixture is condensed, 30 ml. of ethanol and 50 ml. ofacetic acid are added. The mixture is then poured into 700 ml. of water.Extraction with ether gives methyl3-hydroxy-2-methyl-5-nitro-3-indenylacetate.

B. Methyl 5-dimethylamino-2-methyl-3-indenylacetate A solution of 0.05mole of methyl 3-hydroxy-2- methyl-5-nitro-3-indenylacetate, 0.2 mole of38 percent aqueous formaldehyde and 2 ml. of acetic acid in ml. ethanolis reduced catalytically in the presence of a 10% Pd/C catalyst under 40lb. p.s.i. hydrogen pressure at room temperature. The solution isfiltered, evaporated and chromatographed on 300 g. of silica gel to givemethyl 5-dimethylamino-3-hydroxy-2-methyl-3- indenylacetate. The hydroxyester is then dehydrated to methyl5-dimethylamino-2-methyl-3-indenylacetate.

C. 1-p-Methylthiobenzylidene-5-dimethylamino-2- methyl-3-indenyl aceticacid To a solution of 2.5 g. of the ester from Part B of this example in15 ml. of 1,2-dimethoxyethane at 0 is added 1.5 g. ofp-methylthiobenzaldehyde followed by 1.1 g. of potassium t-butoxide. Thereaction mixture is kept in the ice-bath for 4 hours and then allowed tostand at room temperature for 18 hours. The mixture is diluted with 15ml. of ether and the potassium salt is filtered. The salt is dissolvedin 30 m1. of water and neutralized with dilute hydrochloric acid to pH6-6.5. The crude acid precipitated is collected by filtration andchromatographed on asilica gel column, using ether-petroleum ether(v./v. 50-100 percent) as eluent to give pure1-p-methylthiobenzylidene15- dimethylamino-2-methyl-3-indenylacetic acidwhich may be oxidized to l-p-methylsulfinylbenzylidene-5-dimethy1amino-2-methyl-3-indeny1acetic acid andl-pmethylsulfonylbenzylidene-5-dimethylamino-2-methyl- 3-indenylaceticacid as described above.

EXAMPLE 5 a-[1-(p-Methylsulfinylbenzylidene)-2-methyl-5-dimethylamino-3-indenyl]-propionic acid The procedure of Examples 2A, Band C is followed using 6-dimethylamino-2-methylindanone in place of6-methoxy-2-methy1indanone and methyl abromopropionate in place ofmethyl bromoacetate used therein. There is obtained a-[l-(p-methylsulfinylbenzylidene)-2-methyl-5-dimethylamino-3-indenyl]-propionic acid.

EXAMPLE 6 A. 3 ,4-Difluorobenzaldehyde In a 250 ml. three-necked flaskequipped with a magnetic stirrer, thermometer, condenser, and droppingfunnel is placed 25.6 g. (0.2 mole) of 3,4- difluorotoluene. The liquidis heated to 105 and illuminated as 67 g. (0.42 mole) of bromine isadded slowly. The temperature is kept between 105l10 while the firsthalf of the bromine is added over a period of 1 hour. The rest of thebromine is added over approx. a 2 hour period and the temperature israised to 150 and kept there for minutes. The reaction mixture is cooledand transferred to a 1 liter 3-necked flask with a motor driven stirrerand condenser. 120 ml. H 0 and 90 g. of calcium carbonate is added andthe mixture is refluxed for hours with good stirring. The reactionmixture is steam distilled until no further oil is collected. The oil istaken up in methylene chloride and dried over MgSO Evaporation of the.solvent yields 3 ,4-difluorobenzaldehyde which is used without furtherpurification.

B. 3,4-Difluoro-a-methylcinnamic acid A mixture of 2.88 g. (0.02 mole)of 3,4- difluorobenzaldehyde, 3.24 g. (0.025 mole) of propionicanhydride and 0.92 g. (0.02 mole) of sodium propionate under nitrogen isheated at 135 with magnetic stirrer for 20 hours. The reaction mixtureis poured onto 50 ml. of water. A solid precipitates which dissolveswhen 50 ml. of saturated K CO is added with stirring. The basic solutionis extracted with ether (2 X 100 ml.). The aqueous phase is then pouredinto an excess of concentrated HCl and ice. The precipitated white solidis filtered and dried to give 3,4-difluoro-amethylcinnamic acid, m.p.l22l 25. 4-Trifluoromethyl-a-methylcinnamic acid The above reaction ofExample 6A is repeated except that 4-trifluoromethylbenzaldehyde is usedas a starting material in place of 3,4-difluorobenzaldehyde. Using thesame reaction conditions and techniques there is obtained4-trifluoromethyl-a-methylcinnamic acid.

Similarly using other benzaldehydes such as 4- methylthiobenzaldehyde,4-chlorobenzaldehyde, and 3-methyl-4-chlorobenzaldehyde, there isobtained 4- methylthio-a-methylcinnamic acid, 4-chloro-a-methylcinnamicacid and 3-methyl-4-chloro-a-methylcinnamic acid respectively.

C. 3,4-Difluoro-a-methylhydrocinnamic acid 28 G. (0.141 mole) of3,4-difluoro-a-methylcinnamic acid, 1 g. of PtO in 250 ml. of MeOH ishydrogenated at 45 p.s.i. until the theoretical uptake is completed. Thecatalyst is filtered off and the material evaporated to one-third itsvolume. A 15 percent potassium hydroxide solution (10 ml.) is added andthe mixture refluxed for 30 minutes when it is poured into water andextracted with ether (2 X 100 ml.). The aqueous layer is acidified withconcentrated HCl and ice. The oil which comes out is extracted intoether, the ether solution dried over MgSO, and evaporated to leave aclear oil which crystallizes. 3,4-Difluoro-amethylhydrocinnamic acid,m.p. 5556, is isolated.

D. 5,6-Difluoro-2-methyl-l-indanone 20 G. (0.1 mole) of3,4-difluoro-a-methylhydrocinnamic acid is added to 250 g. ofpolyphosphoric acid. The mixture is efficiently stirred and heated on asteam bath for 2 hours. The mixture is poured onto ice-water (400 ml.).The precipitate is extracted with ether (3 X 100 ml.). The extract iswashed with saturated potassium carbonate, water and then dried (MgSOThe ether solution when evaporated leaves solid 5,6-difluoro-2-methyl-1-indanone (m.p. 66-68) which is used without furtherpurification.

E. 5,6-Difluoro-2-methylindene-3acetic acid methyl ester A mixture of9.1 g. (0.05 mole) of 5,6-difluoro 2- methyl-l-indanone, 4.0 g. ofactivated zinc dust, 7.6 g. (0.05 mole) of methyl bromoacetate and acrystal of iodine in 250 ml. of dry benzene is refluxed for 4-5 hours.Tlc (20% Et O pet. ether on Si gel) shows greater than percentconversion at this time. The reaction mixture is poured onto 250 ml. of5% l-l- SO separated, and dried (MgSO Removal of solvent leaves an oilyhydroxy ester. The crude ester is redissolved in ml. of benzene andphosphorus pentoxide (20 g.) is added. The mixture is refluxed for 30minutes (no stirrer necessary) and decanted. The residue is washed withbenzene, the organic layers combined, washed with water (2 X 100 ml.)and dried (MgSO The benzene when evaporated leaves 5,6-difluoro-2-methylindene-3acetic acid methyl ester, m.p. 8690.5-Methylthio-2-methylindene-3-acetic acid ester The above reaction ofExample 65 is repeated using 5-methylthio-2-methylindanone instead of5,6- difluoro-2-methyl-l-indanone. Using the same conditions andtechniques, there is obtained 5-methylthio-2- methylindene-3-acetic acidmethyl ester.

When an acylamino or sulfamyl indanone is employed as the startingmaterial in the above procedure, the corresponding methyl ester isobtained.

F. 5,6-Difluoro-2'methyl-l pmethylthiobenzylidene)-indene-3-acetic acid1.19 G. (5.0 mmole) of5,6-difluoro-2-methylindene- 3-acetic acid esteris dissolved in 10 ml. of dry pyridine followed by 0.76 g. (5.0 mmole)of pmethylthiobenzaldehyde. The flask is placed under nitrogen and 5.0g. (5.1 mmole) of Triton B is added. The deeply colored solution isallowed to stand overnight and then 2 ml. of water is added. Afterstanding for 15 minutes it is poured into an excess of water. Theorganics are extracted with ether (2 X 50 ml.). The aqueous phase isadded to 10% HCl-ice. The orange gummy solid which precipitates isextracted into methylene chloride and dried (MgSO The solvent is 1removed to leave an orange solid. The solid is filtered to give a crudeproduct which is recrystallized'from benzene to give5,6-difluoro-2-methyl-l-(pmethylthiobenzylidene)-indene-3-acetic acid,m.p. 181-182.5.

When 3-methylthio-2-furaldehyde or 2-methylthio- S-pyrazine aldehyde isutilized in the above procedure instead of p-methylthiobenzaldehyde thecorresponding indene acetic acid is obtained.

When the appropriately substituted furans, thiophenes, pyroles,oxazoles, thiazoles, imidazoles,

pyridines, pyridazines, pyrrimidine, pyrazine, piperazine or fusedheterocyclic system is introduced according to the above procedure, thecorresponding l(hetero)-indene-3-acetic acid is obtained.

G. 5,6-Difluoro-2-methyll-(pmethylsulfinylbenzylidene)-indene-3 -aceticacid To a solution of 0.358 g. (1.0 mmole) of 5,6-difluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-acetic acid inacetone ml.) is added 10-15 ml. MeOl-l. With magnetic stirring 0.32 g.(1.5 mmole) of sodium meta periodate is added in 5 ml. of water. Theproportions of acetone, methanol and water are adjusted if necessary inorder to preserve homogeneity. After several minutes, a precipitation ofsodium iodate appears. The suspension is stirred at room temperature for16 hours and then poured into approximately 50 ml. of water and 100 ml.methylene chloride. The two phases are separated and extracted twicewith methylene chloride. The organic layer is washed with water anddried (MgSO The residue after evaporation is dissolved in the minimumamount of boiling ethyl acetate and allowed to stand for 12 hours in thefreezer compartment. The deep orange crystals are filtered. The filtrateis reduced to one-half volume and allowed to stand in the cold forseveral hours to give a large second crop. ln this way,5,6-difluoro-2-methyl-l (p-methylsulfinylbenzylidene)-3-indenylaceticacid is isolated, m.p. 209-2l0.

EXAMPLE 75,6-Difluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-indene-3-aceticacid To5,6-dif1uoro-2-methyl-l-(p-methylsulfinylbenzylidene)-indene-3-aceticacid (0.005 mole) in acetone ml.) is added, slowly with stirring,m-chloroperbenzoic acid (0.005 mole). The mixture is heated andevaporated to near dryness at 40. The solid is leached with boilingwater (4 X 50 ml.) and dried yielding 5,6-difluoro-2-methyl-l-(p-methylsulfonylbenzylidene )-indene-B-acetic acid,m.p. 228-230.

a-[1-(p-Methylsulfinylbenzylidene)-2-methyl-5,6-difluoro-3-indenyl]-propionic acid and a-[l-(p-methylsulfonylbenzylidene)-2-methyl-5,6-dif1uoro-3-indenyll-propionicacid are prepared by the procedures of Examples 3A, B and C.

EXAMPLE 8 A. 3,4-Difluorobenzaldehyde 57 G. (0.5 mole) ofortho-difluorobenzene in 250 ml. of methylene chloride is added to 100g. (0.75 mole) of anhydrous aluminum chloride. The mixture is stirred(motor) and cooled in an ice bath while 85.5 g. (0.75 mole) ofdichloromethyl methylether is added dropwise. Vigorous HCl evolutiontakes place and the reaction mixture turns orange-red. After theaddition the mixture is stirred at room temperature for 15 minutes andthe liquid phase is decanted into 500 ml. of ice and water. Theunreacted residue of aluminum chloride is washed with methylene chlorideuntil colorless and the washings are added to the water. The mixture isshaken well in a separation funnel until the methylene chloride layer isgreen. The organic layer is washed with saturated potassium carbonatesolution until neutral, then dried (MgSO and distilled to give3,4-difluorobenzaldehyde, b.p. 74/20 min. The dark residue in thedistillation pot solidifies on cooling to give His-(3,4-difluorophenyl)methane, m.p. -96. 3,4-Dimethylbenzaldehyde The abovereaction of Example 6A is repeated except that o-xylene anddichloromethyl methylether are the starting materials. Using the samereaction conditions and techniques, there is obtained 3,4-dimethy1-benzaldehyde. 4-Mercaptobenzaldehyde The above reaction of Example 6A isrepeated except that the starting materials are mercaptobenzene anddichloromethyl methylether. Using the same reaction conditions andtechniques, there is obtained 4- mercaptobenzaldehyde.

B. 5,6-Difluoro-2-methyl-]-(pmethylsulfinylbenzylidene)-3-indenyl aceticacid The reactions of Example 68, 6C, 6D, 6E, 6F and 66 are repeated and5,6-difluoro-2-methyl-l-(p-methylsulfinylbenzylidene)- 3-indenyl aceticacid is obtained.

EXAMPLE 9 A. 3-Fluoro-4-methoxybenzaldehyde To a solution ofo-fluoroanisole, 101 g. (0.80 mole) in 500 ml. dry methylene chloride isadded dropwise over 30 minutes a solution of titanium tetrachloride, 182g. (0.96 mole, 1.2 equiv.) and a,a-dichloromethylmethyl ether, g. (0.96mole) in an equal volume of methylene chloride. The temperature ismaintained at 1020C. with an ice-bath. The mixture is stirred at roomtemperature for 1 hour longer and then poured over crushed ice-waterwith stirring. Ether (l 1.) is added and the mixture stirred undernitrogen until solution occurs. The organic layer is extracted withwater (3X), sodium bicarbonate solution (3X) and dried (MgSO The solventis evaporated off at 30 to give crude product as an oil. The oil isvacuum distilled through a jacketed Vigreux column when it gives 3-fluoro-4-methoxybenzalde-hyde, b.p. 121C. at 10 mm. Hg; R, 0.6 on asilica-gel G plate with methylene chloride.

B. 3-Fluoro-4-methoxy-a-methylcinnamic acid A mixture of3-fluoro-4-methoxybenzaldehyde, 34.2 g. (0.22 mole), propionicanhydride, 50 g. (0.38 mole) and sodium propionate, 21 g. (0.22 mole),is stirred under nitrogen at C. for 15 hours. The reaction mixture isthen poured into 1.3 l. of water with stirring and the productprecipitated. 2.0 N potassium hydroxide solution (500 ml.) is added andthe mixture stirred for several hours, until the acid has dissolved.

The aqueous solution is extracted with ether (3X) and then acidifiedwith concentrated hydrochloric acid with stirring. The precipitatedproduct is collected, washed thoroughly with water and dried in a vacuumoven at 50C. over potassium hydroxide pellets to give3-fluoro-a-methyl-4-methoxycinnamic acid, m.p. 167-l69C.; R, 0.5 onsilica gel G with methylene chloride-methanol (1:1).

C. 3-Fluoro-4-methoxy-aacid dihydrocinnamic acid3-Fluoro-4-methoxy-a-methylcinnamic acid, 49.5 g. (0.236 mole) in 800ml. methanol is hydrogenated at 43 lbs. pressure and room temperatureuntil the theroretical uptake of hydrogen has occurred (24 min. at C.,using 1.5 g. platinum oxide catalyst). The solution is filtered and thenevaporated with warming to 60 to give 3-fluoro-4-methoxy-a-methyldihydrocinnamic acid, R, 0.5 on silica-gel G with methylenechloride-methanol (9:1).

D. 5-fluoro-6-methoxy-2-methylindanone A mixture of3-fluoro-a-methyl-4-methoxy dihydrocinnamic acid, 49.3 g. (0.23 mole) in500 g. of polyphosphoric acid is heated at 95C. on a steam bath withoccasional agitation for 75 min. The dark red solution is poured into3.0 l. of water and the mixture stirred overnight. The precipitatedproduct is collected, washed thoroughly with water and then taken up inether. The ether solution is extracted with aqueous potassiumbicarbonate (4X), diluted with methylene chloride and dried (MgSO Theorganic solution is evaporated and recrystallized from methylenechloride-petroleum ether to give 5- fluoro-6-methoxy-2-methylindanone,(m.p. 76-78).

E. Methyl 6-fluoro-5-methoxy-2-methyl-3- indenylacetate Into a 500 ml.three-necked flask fitted with mechanical stirrer, reflux condenser,drying tube, dropping funnel and nitrogen inlet is placed 8.0 g. zincsheet and 100 ml. of dry benzene. A few milliliters of a solution of21.3 g. (0.1 1 mole) of 5-fluoro-6-methoxy-2 -methylindanone and 18.36g. (0.121 mole) of methyl bromoacetate in 100 ml. of dry benzene isadded at a time. A crystal of iodine is added. The mixture is gentlyheated with stirring. After the iodine color has disappeared, theremainder of the mixture is added gradually. The reaction is heated atreflux temperature for 18 hours. The mixture is poured onto 600 ml. of5% H SO and about 500 g. of ice. Some ether is added. The organic layeris separated and washed with three portions of 5% H SO water, KHCOsolution and finally water again. The organic layer is dried (MgSO andconcentrated to give 27.6 g. of reddish oil which crystallizes uponstanding. Thin-layer chromatography on silicagel G with methylenechloride methanol (99:1) shows product at R,(0.5

Without further purification, the hydroxy ester is dehydrated to theindenylacetate. In 200 ml. of dry benzene, 14.2 g. (53 mmole) of crudeester and 36 g. of phosphorus pentoxide are refluxed with stirring forone-half hour. After cooling, the reaction mixture is filtered and thesolid residue washed well with benzene. The benzene filtrate is washedwith two portions of salt water and dried (MgSO The organic solution isconcentrated and gives a slightly colored oil which rapidlycrystallizes. The crude product is recrystallized from methylenechloride-petroleum ether to give methyl-6-fluoro-S-methoxy-2-methyl-3-indeny1acetate (m.p. 61-62).

F.6-Fluoro-5-methoxy-2-methyl-l-(pmethylthiobenzylidene)-3-indenylaceticacid To a solution of methyl-6-fluoro-5-methoxy-2- methyl-3-indenylacetate, 9.3 g. (0.037 mole) and pmethylthiobenzoaldehyde, 6.3 g. (1.1equivalent) is added 16 ml. (2.0 equivalents) of 25 percent methanolicsodium methoxide. The mixture is stirred at reflux under nitrogen for 2hours. An equal volume of water is added dropwise and refluxingcontinues for 30 minutes. The solution is cooled, diluted with water andextracted with ether (3X). Residual ether is blown off with nitrogen andthen the aqueous solution is acidified with 50 percent glacial aceticacid. The precipitated product is collected and washed thoroughly withwater. The crude product is recrystallized from methanol to give 6-fluoro-S-methoxy-2-methyl-l-(p-methylthiobenzy- 1idene)-3-indenylaceticacid, m.p. l72-l 74.

G. 6-Fluoro-5-methoxy-2-methyl- 1-(pmethylsulfinylbenzylidene)-3-indenylacetic acid A solution of sodiumperiodate, 4.28 g. (20 mmole) in 40 ml. of water is added dropwise to6-fluoro-5- methoxy-Z-methyl-l-(p-methylthiobenzylidene)-3-indenylaceticacid, 3.70 g. (10 mmole) in 300 m1. methanol and enough acetone to causesolution. This solution is stirred overnight at room temperature andfiltered. The filtrate is evaporated at 30 to a small volume whichcauses the product to precipitate. The suspension is diluted withseveral volumes of water, cooled and collected. After rinsing with waterand cold methanol-water (1:1), the product is dried in vacuo overpotassium hydroxide pellets and then in a vacuum oven at C. The crudeproduct is recrystallized from methylene chloride-petroleum ether togive 6-fluoro-5- methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3indenylacetic acid (m.p. 190-193).

6-Fluoro-5-methoxy-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetic acid is prepared according to the procedureof Example 7 by the addition of 1.0 mole of m-chloroperbenzoic acid permole of 6- fluoro-S-methoxy-2-methyll -(p-methylsulfinylbenzy-1idene)-3-indeny1 acetic acid in an acetone solution.

a-[ l-(p-Methylsulfinylbenzylidene)-2-methyl-5-fluoro-6-methoxy-3-indeny1]-propionic acid and a-[l-(p-methylsulfonylbenzylidene)-2-methyl-5-methoxy-6-fluoro-3-indenyl]-propionic acid are prepared by the procedures ofExamples 3A, 3B and 3C.

EXAMPLE 10 A. p-Fluoro-a-methylcinnamic acid p-Fluorobenzaldehyde (200g., 1.61 mole), propionic anhydride (3.5 g., 2.42 mole) and sodiumpropionate (155 g., 1.61 mole) are mixed in a 1 l. three-necked flaskwhich had been flushed with nitrogen. The flask is heated gradually inan oil-bath to 140". After 20 hours the flask is cooled to and pouredinto 8 1. of water. The precipitate is dissolved by adding potassiumhydroxide (302 g.) in 2 l. of water. The aqueous solution is extractedwith ether, and the ether extracts washed with potassium hydroxidesolution. The combined aqueous layers are filtered, acidified withconcentrated HCl, filtered and the col lected solid washed with water,thereby producing pfluoro-a-methylcinnamic acid which is used asobtained.

B. p-Fluoro-a-methylhydrocinnamic acid To p-fluoro-a-methylcinnamic acid(177.9 g., 0.987 mole) in 3.6 1. ethanol is added 11.0 g. of Pd/C andthe mixture reduced at room temperature under a hydro-gen pressure of 40p.s.i. Uptake is 31/32 lbs. (97 percent of theoretical). After filteringthe catalyst, the filtrate is concentrated in vacuo' to give the productpfluoro-a-methylhydrocinnamic acid used without weighing in next step.

C. 6-Fluoro-2-methylindanone To 932 g. polyphosphoric acid at 70 on thesteam bath is added p-fluoro-a-methylhydrocinnamic acid (93.2 g., 0.5mole) slowly with stirring. The temperature is gradually raised to 95C.,and the mixture kept at this temperature for 1 hour. The mixture isallowed to cool and added to 2 l. of water. The aqueous layer isextracted with ether, the ether solution washed twice with saturatedsodium chloride solution, 5% Na cO solution, water, and then dried. Theether filtrate is concentrated with 200 g. silica-gel, and added to afive pound silica-gel column packed with 5 percent etherpetroleum ether.The column is eluted with 5-10 percent ether-petroleum ether andfollowed by tlc to give 6-fluoro-2-methylindanone.

D. 5-Fluor0-2-methylindene-3-acetic acid A mixture of6-fluoro-2-methylindanone (18.4 g., 0.112 mole), cyanacetic acid (10.5g., 0.123 mole), acetic acid (6.6 g.), and ammonium acetate (1.7 g.) indry toluene (15.5 ml.) is refluxed with stirring for 21 hours, as theliberated water is collected in a Dean Stark trap. The toluene isconcentrated and the residue dissolved in 60 m1. of hot ethanol and 14ml. of 2.2 N aqueous potassium hydroxide solution. 22 G. of 85% KOH in150 ml. of water is added and the mixture refluxed for 13 hours under NThe ethanol is removed under vacuum, 500 ml. water added, the aqueoussolution washed well with ether and then boiled with charcoal. Theaqueous filtrate is acidified to pH 2 with 50 percent hydrochloric acid,cooled and the precipitate collected. In this way dried5-fluoro-2-methylindenyl-3 -acetic acid (m.p. l64-166) is obtained.

E. 5-Fluoro-2-methyl-1-(p-methylthiobenzylidene)3- indenyl-acetic acid5-Fluoro-2-methyl-3-indenylacetic acid 15 g., 0.072 mole)p-methylthiobenzaldehyde 14.0 g., 0.091 mole) and sodium methoxide (13.0g., 0.24 mole) are heated in methanol (200 ml.) at 60 under nitrogenwith stirring for 6 hours. After cooling the reaction mixture is pouredinto 750 ml. of ice-water, acidified with 2.5 N hydrochloric acid andthe collected solid triturated with a little ether to produce5-fluoro-2-methyl-1-(pmethylthiobenzylidene)-3-indenylacetic acid (m.p.l87-188.2). U.V. in methanol )1 max. 348 my" (E% 500), 258 (557), 258(495), 353 (513), 262.5 (577), 242.5 (51 1).

F. 5-Fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)- 3-indenylaceticacid To a solution of5-fluoro-2-methyl-1-(pmethylthiobenzylidene)-3-indenylacetic acid (3.4g., 0.01 mole) in a mixture of methanol (250 ml.) and acetone ml.) isadded a solution of sodium periodate (3.8 g., 0.018 mole) in water (50ml.) with stirring.

Water (450 ml.) is added after 18 hours and the organic solvents removedunder vacuum below 30. The precipitated product is filtered, dried andrecrystallized from ethyl acetate to give5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indenylacetic acid.Upon repeated recrystallization upon ethylacetate there is obtainedcis-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid, m.p. 184-186. U.V. in methanol; )tmax. 328 (13% 377), 286, (432),257.5 shldr. (413), 227 (548).

Further runs reveal the existence of a second polymorph ofcis-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylaceticacid, m.p. 17918l C.

5-Chloro-2-methyl-1-(p-methylsulfinylbenzylidene)- 3-indenylacetic acidis prepared by the procedure as described above in Example 10.

5 -Fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acidis prepared according to the procedure of Example 7 by the addition of1.0 mole of m-chloroperbenzoic acid per mole of 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid in anacetone solution.

a-[ 1-(p-Methylsulfinylbenzylidene)-2-methyl-5-fluoro-3-indenyl]-propionic acid anda-[l-(p-methylsul-fonylbenzylidene)-2-methyl-5-fluoro-3-indenyl]-propionic acid are prepared by the procedures of Examples 3A, 3B, and3C.

EXAMPLE 1 l A. 2,4-Difluorobenialdehyde A 250 ml., three-necked flask isfitted with a stirrer, a thermometer, a dropping funnel with a long stemto the bottom of the flask and a reflux condenser with a tube leading tothe back of the hood. 50 G. (0.38 mole) of 2,4-difluorotoluene is heatedto reflux with stirring and irradiated with a Hanovia ultraviolet lamp.41.5 ml. of bromine is gradually added. The reaction is completed in 2.5hours during which time the reflux temperature rises from 112 to 155.

A 2 1., three-necked flask is fitted with stirrer and reflux condenser.In the flask is placed 200 ml. of water and g. calcium carbonate. Thecooled abovedescribed reaction mixture is transfered using some etherfor rinsing. The hydrolysis is completed by refluxing with stirring for18 hours. The aldehyde is isolated by steam distillation from thereaction flask. The oil is separated and the aqueous phase is extractedonce with ether. The combined oil and ether extract is dried overanhydrous MgSO, and concentrated under reduced pressure to leave2,4-difluorobenzaldehyde still containing some ether which is distilledthrough a short Vigreux column under reduced pressure and separated intoseveral fractions. These are combined to give 2,4 difluorobenzaldehyde,b.p. 5658/12 mm.

B. 2,4-Difluoro-ix-methylcinnamic acid A 500 ml., three-necked flask isfitted with reflux condenser, drying tube, stirrer and N inlet. To amixture of 55.4 g. (0.39 mole) of 2,4-difluorobenzaldehyde and 56 ml. ofpropionic anhydride is added 38 g. (0.39 mole) of sodium propionate. Thereactionmixture is heated at 135- 140 (oil bath temp.) for 19 hours withstirring under nitrogen. The still warm solution is poured into 1 l. ofwater with stirring. A solid separates which upon adding 56 g. ofpotassium hydroxide dissolves. The solution is extracted with ether andthen heated on the steam bath to remove the ether. After cooling in anice-bath, concentrated hydrochloric acid is added with stirring. Theproduct which separates is collected and washed with cold water. Afterdrying at 60 over KOH 2,4-difluoro-amethylcinnamic acid, m.p. 126-128 isobtained.

C. 2,4-Difluoro-a-methyldihydrocinnamic acid In 800 ml. of methanol, 60g. (0.3 mole) of 2,4- difluoro-a-methylcinnamic acid with 1.5 g. ofplatinum oxide catalyst is shaken under an initial pressure of 42 lbs.of hydrogen until one equivalent of hydrogen is absorbed. The reactiontime is 30 minutes. The catalyst is removed by filtration and washedwith methanol. The methanol, when evaporated off, leaves near colorless2,4-difluoro-a-methyldihydrocinnamic acid as an oil which is used in thenext step without further purification.

D. 4,6-Difluoro-2-methy1indanone A solution of2,4-difluoro-a-methyldihydrocinnamic acid, 54.8 g. (0.274 mole) in 125ml. thionyl chloride is stirred for 90 minutes and then at reflux for 90minutes longer. The reaction solution is evaporated under reducedpressure leaving the acid chloride product as an oil.

To a suspension of ice-bath cooled anhydrous powdered aluminum chloride,60 g. (0.45 mole), in 250 ml. of dry carbon disulfide is added dropwiseover 10 minutes, a solution of the acid chloride, 60 g., in 100 ml.carbon disulfide. After the addition the ice bath is removed and thetemperature raised slowly to room temperature. The mixture is stirred atroom temperature for 20 hours and then is poured into 2 l. of 10 percentaqueous hydrochloric acid crushed ice with stirring. Ether is added andthe stirring continued until everything dissolves. The ether layer isextracted with 5 percent hydrochloric acid (2X), water (2X), and sodiumbicarbonate solution (2X), when it is diluted with methylene chlorideand dried (MgSO.). The filtered solution is evaporated'with warming to70C. to give the crude 4,6-difluoro-a-methylindanone as an oil whichcrystallizes on standing. The crude product is purified bychromatography of a column (7.0 X 35 cm.) of silica-gel, 400 g. of J.T.'Baker 3405 packed in petroleum ether-methylene chloride (2:1). Thecolumn is developed and eluted with the same solvent system and uponrecrystallization from methylene chloridepetroleum ether gives4,6-difluoro-2-methylindanone, m.p. 6869C.

E. Methyl 5,7-difluoro-2-methylindcnyl-3-acetate About 20 percent of asolution containing 4,6- difluoro-2-methylindanone, 15.0 g. (83 mmole),and methyl bromoacetate, 14.0 g. (1.1 equiv.) in ml. dry benzene isadded to a stirred suspension of powdered zinc dust (Merck dried l20l20mm.), 6.5 g. (1.2 equiv.) in 74 m1. dry benzene under a nitrogenatmosphere. Several crystals of iodine are added and the mixture slowlybrought to reflux. The remainder of the solution is added dropwise over10 minutes and the mixture stirred at reflux overnight, i.e., 17 hours.The reaction is cooled to room temperature, the mixture poured into2.0 1. of 20 percent aqueous sulfuric acid crushed ice with stirring,and ether added until a clear solution is obtained. The ether layer isextracted with 5% aqueous sulfuric acid (3X), water (3X), diluted withmethylene chloride and dried (MgSO The filtered ethereal solution isevaporated to give crude hydroxy ester.

Powdered phosphorus pentoxide (60.0 g.) is added to the hydroxy ester(20.0 g.) in 400 ml. of dry benzene. The mixture is stirredat reflux for30 minutes and the clear benzene solution decanted. The residue isrinsed with benzene and then with ether. The combined organic solutionsare diluted with ether, extracted six times with aqueous sodium sulfatesolution, twice with aqueous potassium bicarbonate solution, diluted,with methylene chloride and dried (MgSO The crude indenyl acetateproduct is obtained by evaporation of the filtered elution to give anoil. The product is crystallized from petroleum ether and gives methyl5,7- difluoro-Z-methylindenyl-3-acetate, m.p. 6970C.

F. 5,7-Difluoro-2-methyl-l-(pmethylthiobenzylidene)-3-indenylaceticacid, a mixture of geometric isomers Powdered sodium methoxide, 2.2 g.(40 mmole) is added to a suspension of methyl 5,7-difluoro-2-methylindenyl-3-acetate (4.78 g.) (20 mmole) andpmethylthiobenzaldehyde, 3.35 g. (22 mmole), in 40 ml. dry methanolunder nitrogen. A clear solution results which is refluxed for 60minutes. An equal volume of water is added and refluxing continued undernitrogen for 30 minutes to complete saponification. The solution isdiluted with several volumes of water and extracted with ether. Nitrogenis bubbled through the aqueous solution to remove the residual ethersolvent. Fifty percent aqueous acetic acid (40 ml.) is used toprecipitate the product. The product is collected and washed well withwater then it is dried in a desiccator over potassium hydroxide pelletsand finally in the oven at 100. The crude product is recrystallized frommethylene chloride-petroleum ether and gives the cis and trans mixtureof acids, m.p. l64-173 in a 1:3 ratio, identifiable by integrating the2-Cl-l signal in the N.M.R. spectra at 7.827 for cis and 8.207 fortrans. v

G. Cis-methyl-5,7-difluoro-2-methyl-1pmethylthiobenzylidene)-3-indenylacetate isolation by columnchromatography Four drops of concentrated sulfuric acid is added to asolution of S ,7-difluoro-2-methyllpmethylthiobenzylidene)-3-indenylacetic acid, 1.0 g. (2.8 mmole) in 60ml. of dry methanol and the solution stirred at reflux overnight. Thesolution is cooled and crystals separated which are collected, rinsedwith cold methanol-water (1:1) and dried over potassium hydroxidepellets. These crystals are found to be ca. 95 percent of thetrans-isomer and could be further purified by recrystallizing frommethanol giving the transisomer, m.p. 106106.5C. Powdered potassiumbicarbonate is added to the filtrate from the first crop of crystals,followed by water. A second crop of mixed ester is obtained in this waywhich is cis-enriched and used for chromatography.

1.7 G. of cis and trans-mixed esters are chromatographed ona column (3.0X 90 cm.) of silica-gel, 250 g. of J.T. Baker 3405, packed in methylenechloridepetroleum ether (1:9). The column is developed and eluted with a1:4 ratio of the same solvents. 0.3 to 0.4 l. cuts are taken as theyellow bands are eluted. In this way the trans-isomer and the cis-isomer(m.p. 94-95) are obtained; U.V. of trans in MeOH Amax. 217 m;r., 256 and362 mu; U.V. of cis-isomer in MeOH A max. 218 mph, 260 and 357 mu.

Cis-Cis.-,7-difluoro-2-methyl-1-(pmethylthiobenzylidene)-3-indenylacetic acid 1.Cis-S,7-difluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indenylaceticacid Sodium periodate 214 mg. (1.0 mmole) in 2 ml. water is added tocis-5,7-difluoro-2-methyl-l-(pmethylthiobenzylidene)-3-indenylaceticacid, 170 mg. (0.475 mmole) in 12 ml. of methanol and ca. 0.5 ml.acetone at room temperature. The mixture is stirred overnight wheninspection of the tlc on silica-gel G using methylene chloride-methanolelution (1:1 shows that there is not starting material present but atrace of sulfone at R, 0.55. The reaction mixture is filtered andconcentrated to a small volume without heating and diluted with water.The product is collected, rinsed with water and dried over potassiumhydroxide pellets in a vacuum dessicator and finally in the ovendessicator at 80. The product is recrystallized from ethylacetate-petroleum ether and gives pure cis-5,7-difluoro-Z-methyl-l-(p-methylsulfinylbenzylidene)-3- indenylacetic acid,m.p. 188-l 89C.

EXAMPLE 12 A. Cis-methyl-S,6-difluoro-2-methyl-l-(pmethylthiobenzylidene)-3-indenylacetate Four drops of concentratedsulfuric acid is added to a solution of5,6-diflu0ro-2-methyl-l-(pmethylthiobenzylidene)-3-indenylacetic acid,1.0 g. (2.8 mmole) in 60 ml. of dry methanol and the solution stirred atreflux overnight. The solution is cooled and crystals separated.Powdered potassium bicarbonate and water are added to the filtrate. Thecis and trans-' mixed esters are chromatographed on a column (3.0 X cm.)of silica-gel, 250 g. of 1.1". Baker 3405, packed in methylenechloride-petroleum ether (1.9). The column is developed and eluted witha 1:4 ratio of the same solvents. 0.3 to 0.4 l. cuts are taken as theyellow bands are eluted. In this way the trans-isomer and the cis-isomerare obtained.

B.Cis-5,6-difluoro-2-methyl-1-(pmethylsulfinylbenzylidene)-3-indenylaceticacid EXAMPLE 13 5 -Flu0ro-2-methyl1-(p-methylsulfinylbenzylidene)-3-indenylacetmorpholide A mixture of5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetic acid(0.01 mole) and thionyl chloride (0.03 mole) in a dried flask, condenserand drying tube set-up is heated on the steam bath until evolution ofgas ceases. Excess thionyl chloride is then removed in vacuo, theresidue taken up in a slight excess of anhydrous ether and added slowlyto a vigorously stirred, ice-cooled solution of dry morpholine (0.035mole) in ml. of ether. The mixture is stirred overnight at roomtemperature, filtered, the morpholine hydrochloride washed with excessether, and the combined ether filtrates washed with 2 X 100 ml. water,dried over anhydrous sodium sulfate, filtered, and the ether removed invacuo. Chromatography of the crude product on a silica-gel column, usingv./v. 50100 percent ether in petroleum ether as eluent gives the desiredmorpholide.

Similarly, when morpholine is replaced by an equivalent amount of thefollowing amines, the corresponding amides are obtained.

Dimethylamine Ethanolamine Benzylamine N,N-diethylethylenediamineBenzylglycinate Piperidine Pyrrolidine N-methylpiperazineN-phenylpiperazine N-hydroxyethylpiperazine Piperazine DiethylamineDiethanolamine Aniline p-Ethoxyaniline p-Chloroaniline p-Fluoroanilinep-Trifluoromethylaniline Butylamine 'Cyclohexylamine MethylamineD-glucosamine Tetra-o-acetyl-d-glucosamine D-galactosylamineD-mannosylamine N,N-dimethyl-glycine amide N,N-dibutylglycine amideN-methyl-2-aminomethylpiperidine N-methyl-2aminomethylpyrrolidineB-Ethoxyethylamine Di(B-ethoxyethyl)amine B-Phenethylaminea-Phenethylamine Dibenzylamine D-mannosamine EXAMPLE l4 Esters of5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene )-3-indenylacetic acid(A) Simple Esters A mixture of 0.1 mole of 5- fluoro-2-methyll-(p-methylsulfinylbenzylidene)-3 indenylacetic acid, 0.2 g. of p-toluenesulfonic acid, 100 ml. of absolute ethanol and 75 ml. of dry benzene isrefluxed on a steam bath while slowly distilling the solvent. After 17hours the residual solvent is removed under reduced pressure. Theresidue is slurried in aqueous sodium bicarbonate and then with wateruntil neutral. The resulting ethyl ester may be recrystallized fromorganic solvents such as ethyl acetate, benzene and the like. Whenmethanol, propanol, t-butanol and benzyl alcohol are used instead of theethanol in the above procedure, there is obtained the correspondingmethyl, propyl, t-butyl and benzyl esters.

(B) Alkoxyalkyl Esters Chloromethyl methyl ether (0.055 mole) is addedto a suspension of 5-fluoro-Z-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetic acid(0.05 mole) and anhydrous potassium carbonate (0.15 mole) in 250 ml. ofanhydrous acetone. The mixture is allowed to stir overnight at roomtemperature. Diethyl ether is added (about 200 ml.) and the mixture isfiltered. The filtrate is washed once with 100 ml. of water and driedover anhydrous sodium sulfate. It is then filtered and the solvent isremoved in vacuo. The residue is chromatographed on 200 g. ofacid-washed alumina, using ether-petroleum ether (varying from to 60percent ether by volume) as the eluent, to give methoxymethyl5-fluoro-2- methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetate.

(C) Dialkylaminoalkyl Esters A solution of 0.0054 mole ofN,N-dicyclohexylcarbodiimide in 6 ml. of anhydrous tetrahydrofuran isadded to a solution of 5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3- indenylacetic acid (0.005 mole) and 2-diethylaminoethanol (0.0054 mole) in 17 ml. of anhydroustetrahydrofuran. The mixture is stirred at ambient temperatureovernight. The dicyclohexylurea is removed by filtration and 2 ml. ofglacial acetic acid is added to the filtrate. After the mixture hasstood for one hour, it is filtered and 200 ml. of ether is added to thefiltrate. The solution is then extracted three times with ml. of 2.5 NHCl and the extracts are combined, washed twice with l00 ml. of ether,ice-cooled, made slightly alkaline with concentrated NH 0H and extractedthree times with 100 ml. of ether. The ether extracts are combined,washed ten times with 100 ml. of water to remove traces of startingamine, dried over anhydrous potassium carbonate, filtered, andevaporated in vacuo. The oily residue is B- diethylaminoethyl5-fluoro-2-methyll -(p-methylsulfinylbenzylidene)-3-indenylacetate.

When Z-dimethylaminoethanol, 3-dimethylamino-lpropanol,3-diethylamino-l-propanol, N-B-hydroxyethylpiperidine,N-B-hydroxyethylpyrrolidine, N- hydroxymethylpyrrolidine,N-methyl-2-hydroxymethylpyrrolidine, N-ethyl-Z-hydroxymethylpiperidine,l-B-hydroxyethyl-4'-methylpiperazine or N-B-hydroxyethyl morpholine isused in the above procedure in place of 2-diethylaminoethanol, thecorresponding fl-dimethylaminoethyl, 'ydimethylaminopropyl,y-diethylaminopropyl, B-N- piperidinylethyl, B-N-pyrrolidinylethyl,N-pyrrolidinylmethyl, 2'-( l '-methylpyrrolidinylmethyl),4-methyl-lpiperazinylethyl, N-ethyl-2-piperidinylethyl and N-morpholinylethyl esters are obtained.

(D) Phenyl5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidenyl)-3-indenylacetate Asolution of 0.0054 mole of N,N-dicyclohexylcarbodiimide in 6 ml. ofanhydrous tetrahydrofuran is added to a solution of 5- fluoro-2-methyllp-methylsulfinylbenzylidenyl )-3-indenylacetic acid (0.005 mole) andphenol (0.0054 mole) in 17 ml. of anhydrous tetrahydrofuran. The mixtureis shaken vigorously and allowed to sit, stoppered, at room temperatureovernight.

After filtering off the N,N-dicyclohexylurea, 2 ml. of glacial aceticacid is added to the filtrate and the mixture allowed to stand 1 hour.After filtering, 200 ml. ether is added to the filtrate and the ethersolution washed with 2 X 100 ml. saturated sodium bicarbonate solutionand 3 X 100 ml. water and then dried over anhydrous sodium sulfate. Themixture is filtered, concentrated in vacuo to 25 ml. and chromatographedon a l50 g. acid washed alumina column using etherpetroleum ether (v./v.l0-60 percent) as eluent to give phenyl5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidenyl)-3-indenylacetate.

Similarly, using 2-(2-methoxyethoxy)-ethanol, glycol orN-acetyl-ethanolamine in place of phenyl in the above procedure gives2-(2-methoxyethoxy)-ethyl 5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidenyl)-3-indenylacetate,B-hydroxyethyl5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidenyl)-3-indenylacetate and[3- acetamidoethyl5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidenyl)-3-indenylacetate,respectively.

A mixture of 0.06 mole of sodium 5,6-difluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetate and 0.05 mole oftrityl bromide in 100 ml. anhydrous benzene is refluxed with rapidstirring under nitrogen for 5 hours. The hot reaction mixture isfiltered and the filtrate is concentrated in vacuo. The residual oil isrecrystallized from methyl ethyl ketone to give trityl5,6-difluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetate.

Similarly the phenyl or trityl esters of S-fluoro-Z- methyl- 1-(p-methylsulfinylbenzylidene)-3-indenyl EXAMPLE l5N-[5-fluoro-2-methyllpmethylsulfinylbenzylidene)-3-indenylacetyl]-glycine (A)Benzyl-N-[5-fluor0-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetyl]-glycinateThe procedure of Example 14 is followed using benzylamino acetate inplace of the morpholine to produce the above-named compound. (B)N-[S-fluoro- 2-methyl-l p-methylsulfinyl-benzylidene)-3-indenylacetyl]-glycine Benzyl-n-[5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetyl]- glycinate (0.003 mole)in a mixture of 25 ml. of anhydrous ethanol and 2.5 ml. of 1 N sodiumhydroxide is allowed to stand at room temperature for 18 hours. Thesolution is diluted with water and extracted with ether. The aqueouslayer is acidified with dilute hydrochloric acid and the organic productis extracted with ethyl acetate, washed with water and dried over sodiumsulfate. Evaporation of the solution gives N-[5-fluoro-2 -methyl- 1p-methylsulfinylbenzylidene )-3-indenylacetyll-glycine.

When any of the other 1-aralkylidene-3-indenyl aliphatic acids describedin the other examples of these specifications are used in the aboveprocedure in place of the5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetic acid,the corresponding indenyl acyl glycine is obtained.

EXAMPLE 16 A. Sodium 5-fluoro'2-methyl-l-(pmethylsulfinylbenzylidene)-3-indenylacetate 5 -Fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)- 3-indenylacetic acid (1.79 g.) inmethanol ml.) is added to a solution of sodium methoxide (0.27 g.) inmethanol (5 ml.). The reaction mixture is stirred for minutes andevaporated to dryness to yield sodium 5-fluoro-Z-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetate.

B. Calcium5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indenylacetate Theabove reaction is repeated using 2 moles of acid per mole of calciummethoxide. Using the same reaction conditions and techniques there isobtained calcium 5-fluoro-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indenylacetate.

EXAMPLE 17 A mixture of 250 parts of5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indenylacctic acidand parts of lactose is granulated with suitable water and to this isadded 100 parts of maize starch. The mass is passed through a l6-meshscreen. The granules are dried at a temperature below 60C. The drygranules are passed through a l6-mesh screen and mixed with 3.8 parts ofmagnesium stearate. They are then compressed into tablets suitable fororal administration according to the method of this invention.

LII

What is claimed is: l. A method of treating pain, fever or inflamationwhich comprises administering to a host a therapeutically effectiveamount of a compound.

2. A method of treating pain, fever, or inflamation in.

accordance with the method of claim 1 wherein the compound is of theformula:

I m x/ R? wherein: a R is hydrogen, loweralkyl, or haloloweralkyl;

R, is hydrogen or loweralkyl; R is hydrogen; R is hydrogen, halogen,loweralkoxy, amino,

loweralkylamino or diloweralkylamino; R is hydrogen, halogen,loweralkoxy, amino,

loweralkylamino, or diloweralkylamino; R is hydrogen, halogen,loweralkoxy, amino,

loweralkylamino or diloweralkylamino; R is loweralkylsulfinyl orloweralkylsulfonyl; R,, is hydrogen, halogen, hydroxy, lowcralkoxy,

loweralkyl or halolowcralkyl; and M is hydroxy, loweralkoxy, benzyloxy,phenoxy, or

the group OMe wherein Me is alkali metal or alkali earth metal. 3. Amethod of treating pain, fever, or inflamation in accordance with themethod of claim 1 wherein the compound is of the formula:

29 30 R1 lowerdialkylamino, .lowerdialkylaminoloweralkyl, sulfamyl,loweralkylthio, mercapto, hydroxy, 'WTCHCOOH hydroxyloweralkyl,loweralkylsulfonyl, halogen, RF 1! carboxyl, carbloweralkoxy, carbamido,5 halogenoalkyl, cycloalkyl, or cycloalkoxy; R is alkylsulfinyl oralkylsulfonyl;

R is hydrogen, halogen, hydroxy, alkoxy or haloal- A kyl; and

"1k M is hydroxy, loweralkoxy, benzyloxy, phenoxy, or the group OMewherein Me is alkali metal or alkali earth metal and a pharmaceuticallyacceptable carrier therefore. wherein: 12. A pharmaceutical compositionas in claim 11 R is hydrogen or loweralkyl; wherein the activeingredient is a compound selected R is loweralkyl; from the formula: Ris hydrogen; R is halogen, loweralkyoxy, or diloweralkylamino; R1 R ishydrogen, halogen, loweralkoxy or diloweral- JJIFCOM kylamino; 1] R ishydrogen, halogen, loweralkoxy or diloweralkylamino; I R isloweralkylsulfinyl or loweralkylsulfonyl; and 6 H R is hydrogen. i 4.The method of claim 1 wherein the compound is5,6-difluoro-2-methyl-l-(p-methylsulfinylbenzyj lidene)-3-indene aceticacid. A 5. The method of claim 1 wherein the compound is5-guoro-2-methy(:-l -(p-methylsulfinylbenzylidene)-3- wherein. ll'l eneacetic acl 6. The method of claim 1 wherein the compound is g :zgiggzgxmzz glfi hdloloweralky" a-lS-fluoro-Z-methyllp-methylsulfinylbenzylidene)- hydmgen; 3'mdenyllnproplomc i R ishydrogen, halogen, loweralkoxy, amino,

7. The method of claim 1 wherein the compound 15 loweralkylamino ordfloweralkylamina 5,7-dlfluoro-2-methyl-l-(p-methylsulfinylbenzy- R5 ishydrogen halogen loweralkoxy amino lidene)-3-indene acetic acid.

8. The method of claim 1 wherein the compound is 5-chloro-2-methyl- 1p-methylsulfinylbenzylidene )-3 indene acetic acid.

9. The method of claim 1 wherein the compound is 406-fluoro-5-methoxy-2-methyl-l-(p-methylsulfinylbenzylidene)-3-indeneacetic acid.

10. A method of treating pain, fever, or inflamation which comprisesadministering to a host a therapeutically effective amount ofcis-5-fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indene aceticacid.

11. A pharmaceutical composition for the treatment loweralkylamino, ordiloweralkylamino; R is hydrogen, halogen, loweralkoxy, amino,

loweralkylamino or diloweralkylamino; R is loweralkylsulfinyl orloweralkylsulfonyl; R is hydrogen, halogen, hydroxy, loweralkoxy,

loweralkyl or haloloweralkyl; and M is hydroxy, loweralkoxy, benzyloxy,phenoxy, or

the group OMe wherein Me is alkali metal or alkali earth metal.

13. A pharmaceutical composition as in claim 12 wherein the activeingredient is a compound of the forof pain, fever or inflammationcomprising an effective mula: amount of a compound of the formula R3 {jlltl R1 In rnooou lhdir-t'oM m H l R5 l t ill I it, ("in x ,o- A i Rs l-n-- ll," ltwherein: wherein: R, is hydrogen or loweralkyl;

R, is hydrogen, loweralkyl or halogenated loweral- R, is loweralkyl;

kyl; R is hydrogen; R, is hydrogen or alkyl; R, is halogen, loweralkoxy,or diloweralkylamino; R R R and R each are hydrogen, loweralkyl, R ishydrogen, halogen, loweralkoxy or diloweralloweralkoxy, nitro, amino,loweralkylamino, kylamino;

R, is hydrogen, halogen, loweralkoxy or diloweralkylamino;

R is loweralkylsulfinyl or loweralkylsulfonyl; and

R is hydrogen.

14. A pharmaceutical composition as in claim 13 wherein the compound is5,6-difluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-3-indene aceticacid.

15. A pharmaceutical composition as in claim 14 wherein the compound is-fluoro-2-methyl-l(pmethylsulfinyl-benzylidene)-3 indene acetic acid.

16. A pharmaceutical composition as in claim 15 wherein the compound isa-[S-fluoro-Z-methyl-l-(pmethylsulfinylbenzylidene)-3-indenyl]-propionicacid.

17. A pharmaceutical composition as in claim l6 UNITE STAT @MCTE PatentNo. 3,725,548 v Dated April 3, 1973 Xwsrfimfls) glhen, Greenwald, Jones,Linn and Witzel It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 5, line 3, the first word in the line which 'is "and" should be"the".

Column 6, line 38, the "R group is missing iolumn 6, line 52 whichreads:

"20l20bL in'ether, benzene, toluene, xylene, etc."

should read:

"20-l20 in ether, benzene, toluene, Xylene, etc."

Column 7, the formula appearing in brackets which reads as follows:

should be: 6

TED STATES PATENT OFFICE QEHMCATE "0F (JORRECTION Pat nrN 3.725.548Dated ADriljJl973 Inventor-(B) Shen, Greenwald, Jones, Linn and Witzelii: is certified that error appears in the above-identified patent andthat seid Letters Patent are hereby corrected as shown below:

PAGEZ .1

Column 7, between lines 25-30, the formula on the left hand side whichreads:

should read as follows:

- UNHED' STATES PATENT OFFICE QERTWECATE @F CORRECTION Patent No-3.725.548 Dated April =1. m7;

lnventofls) Shen) Greenwald, Jones, Linn and Witzel It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

in, PAGE 3 Column 8,v line 42, "cm-aryl" should be "B-aryl".

Column 12, line 50, which reads:

"to give pure l-p-methylthiobenzylidenelS-" should be:

"to giverpure l-P-methylthiohenzylidene5" Column 17, line l, whichreads:

"C. 3-Fluoro-4-methoxy-aacid dihydrocinnamic acid" should be:

"C. 3-Fluoro-4-methoxy-a-methyl dihydrocinnamic acid" Column 18, line39, (p-methylsulfinyl-" should be (p-.-methylsu1fonyl-" a Column 23 line23, which reads:

"Cis-Cis-S,7-difluoro-2-methyl-l- (p" should read: v

"H-Cis-S,7-difluoro-2-"methyl-l- (P"" Column 2.37, line 18, "Benzyl-n"should be "Benzyl-N"

2. A method of treating pain, fever, or inflamation in accordance withthe method of claim 1 wherein the compound is of the formula:
 3. Amethod of treating pain, fever, or inflamation in accordance with themethod of claim 1 wherein the compound is of the formula:
 4. The methodof claim 1 wherein the compound is5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene aceticacid.
 5. The method of claim 1 wherein the compound is5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene acetic acid.6. The method of claim 1 wherein the compound is Alpha-(5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl)-propionicacid.
 7. The method of claim 1 wherein the compound is5,7-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene aceticacid.
 8. The method of claim 1 wherein the compound is5-chloro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene acetic acid.9. The method of claim 1 wherein the compound is6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indeneacetic acid.
 10. A method of treating pain, fever, or inflamation whichcomprises administering to a host a therapeutically effective amount ofcis-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene aceticacid.
 11. A pharmaceutical composition for the treatment of pain, feveror inflammation comprising an effective amount of a compound of theformula
 12. A pharmaceutical composition as in claim 11 wherein theactive ingredient is a compound selected from the formula:
 13. Apharmaceutical composition as in claim 12 wherein the active ingredientis a compound of the formula:
 14. A pharmaceutical composition as inclaim 13 wherein the compound is5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene aceticacid.
 15. A pharmaceutical composition as in claim 14 wherein thecompound is 5-fluoro-2-methyl-1-(p-methylsulfinyl-benzylidene)-3-indeneacetic acid.
 16. A pharmaceutical composition as in claim 15 wherein thecompound is Alpha-(5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl)-propionicacid.
 17. A pharmaceutical composition as in claim 16 wherein thecompound is5,7-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene aceticacid.
 18. A pharmaceutical composition as in claim 17 wherein thecompound is 5 -chloro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indeneacetic acid.
 19. A pharmaceutical composition as in claim 18 wherein thecompound is6-fluoro-5-methoxy-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indeneacetic acid.
 20. A pharmaceutical composition comprising apharmaceutically acceptable carrier andcis-5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indene aceticacid.